TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice

Abstract

Although it has been reported that deficiency of toll-like receptor 4 (TLR4) is associated with reduced atherosclerosis in atherosclerosis-prone mice and attenuated pro-inflammatory state in diabetic mice, it remains undetermined whether treatment with a TLR4 antagonist reduces atherosclerosis in nondiabetic or diabetic mice that have TLR4 expression. In this study, we determined the effect ofRhodobacter sphaeroideslipopolysaccharide (Rs-LPS), an established TLR4 antagonist, on early-stage atherosclerosis in nondiabetic and streptozotocin-induced diabetic apolipoprotein E-deficient (Apoe−/−) mice. Analysis of atherosclerotic lesions of both en face aortas and cross sections of aortic roots showed that administration of Rs-LPS in 14-week-old diabeticApoe−/−mice for 10 weeks significantly reduced atherosclerotic lesions. Although atherosclerotic lesions in nondiabeticApoe−/−mice appeared to be decreased by Rs-LPS treatment, the difference was not statistically significant. Metabolic study showed that Rs-LPS significantly lowered serum levels of cholesterol and triglycerides in nondiabetic mice but not in diabetic mice. Furthermore, immunohistochemistry studies showed that Rs-LPS inhibited the expression of interleukin 6 and matrix metalloproteinase-9 and reduced the content of monocytes and macrophages in atherosclerotic plaques. Taken together, this study demonstrated for the first time that TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabeticApoe−/−mice and lowered serum cholesterol and triglyceride levels in nondiabeticApoe−/−mice.